T regulatory cells, also referred to as Treg, function to temper the massive pro-inflammatory stimulus formed by commensal bacteria and dietary antigens within the gut. Evidence of their functional importance at suppressing gut inflammation is observed by the fact that their absence permits the onset of gut autoimmunity (Izcue, et al. (2006) Immunol. Rev. 212:256-271). The manipulation of Treg within the gut, therefore, provides an attractive avenue of therapeutic intervention in enforcing gut tolerance during times when the balance is shifted toward autoimmunity.
The ability of activated T cells to exit the blood and enter different tissues of the body is ‘imprinted’ upon them within the secondary lymphoid organs (SLOs) by dendritic cells (Mora, et al. (2003) Nature 424:88-93; Mora, et al. (2005) J. Exp. Med. 201:303-316). T cells homing to the small intestine lamina propria express the integrin α4β7, which binds mucosal addressin cell adhesion molecule-1 (MAdCAM-1), and the chemokine receptor CCR9, whose ligand is secreted within the lamina propria (Berlin, et al. (1993) Cell 74:185-195; Wagner, et al. (1996) Nature 382:366-370; Zabel, et al. (1999) J. Exp. Med. 190:1241-1256; Mora & von Andrian (2006) Trends Immunol. 27:235-243). A population of dendritic cells (DCs) expressing the integrin CD103+ which reside primarily within the lamina propria, peyer's patches and mesenteric lymph nodes are responsible for imprinting a gut-homing capacity on T cells by an all-trans retinoic acid-dependent mechanism (Izcue, et al. (2006) supra; Annacker, et al. (2005) J. Exp. Med. 202:1051-1061; Johansson-Lindbom, et al. (2005) J. Exp. Med. 202:1063-1073; Iwata, et al. (2004) Immunity 21:527-538). As such, the activation of CD4+ T cells in the presence of all-trans-retinoic acid (RA) induces robust expression of the gut-homing markers α4β7 and CCR9 and a gut-homing capacity in vitro (Iwata, et al. (2004) supra). IL-10 and TGFβ have also been shown to polarize CD4 T cells into Treg cells (Clark & Kupper (2005) J. Invest. Dermatol. 125:629-637).
It has been shown that CD4+FoxP3-naïve T cells can be converted into CD4+FoxP3+ Treg (hereafter referred to as adaptive Treg) exhibiting the same suppressive and phenotypic characteristics as thymically-derived, natural Treg both in vivo and in vitro (Cobbold, et al. (2004) J. Immunol. 172:6003-6010; Chen, et al. (2003) J. Exp. Med. 198:1875-1886; Park, et al. (2004) Int. Immunol. 16:1203-1213; Fantini, et al. (2006) Gut 55:671-680; Ochando, et al. (2006) Nat. Immunol. 7:652-662). This conversion is dependent upon TGFbeta1 and requires high doses of IL-2 (Chan, et al. (2003) supra; Zheng, et al. (2004) J. Immunol. 172:5213-5221; Fantini, et al. (2004) J. Immunol. 172:5149-5153). Further, dendritic cells from mesenteric and peripheral lymph nodes (LN), or retinoic acid and IL-12 have been shown to function as polarizing compounds to induce mucosa- and skin-seeking Treg, respectively (Siewert, et al. (2007) Eur. J. Immunol. 37(4):978-89). Moreover, the use of adaptive Treg as a means of inducing tolerance has been demonstrated in numerous settings including inflammatory bowel disease and transplantation models (Cobbold, et al. (2004) supra; Fantini, et al. (2006) supra; Ochando, et al. (2006) supra; Karim, et al. (2004) J. Immunol. 172:923-928).
Improving the potency of the adaptive reg Treg treatments is of great clinical interest, and harnessing imprinting mechanisms in order to target adaptive Treg to a specific organ in need of immunosuppression is one means to this end.